Because of the countercurrent arrangement of blood flow in the capillaries of the renal medulla, medullary tension is always low, and medullary cells, especially of the thick ascending limb (mTAL), are at special risk of hypoxic injury. We hypothesize that local mechanisms normally operate to feedback and down-regulate transport activity in these cells, in order to protect them from anoxic damage. We therefore intend to investigate autocrine and paracrine substances that may modulate transport of the mTAL. These include adenosine, prostaglandin E2, and other eicosanoids. The effects of these substances on respiration and transport by mTAL tubules and cells, their mechanism of action, and their local production and action in states of increased cellular transport or of hypoxia will be examined. As a counterpoint to these studies, we will investigate the effect of prostaglandins on another species of medullary tubule, the inner medullary collecting duct.